General pharmacology - Pharmacology for Medical Graduates, 4th Updated Edition

Pharmacopoeia : It is a book which contains a list of established and officially approved drugs with description of their physical and chemical characteristics and tests for their identification, purity, methods of storage, etc. Some of the pharmacopoeias are the Indian Pharmacopoeia (IP), the British Pharmacopoeia (BP), and the United States Pharmacopoeia (USP).

Other sources of drug information are National Formulary (NF), Martindale – the Extra Pharmacopoeia, Physician’s Desk Reference (PDR), American Medical Association Drug Evaluation, textbooks and journals of pharmacology and therapeutics, drug bulletins, databases like Micromedex, Medline, Cochrane Library, etc. Information can also be obtained from pharmaceutical companies through their medical representatives, meetings and drug advertisements in journals.

Formulary : It provides information about the available drugs in a country – their use, dose, dosage forms, adverse effects, contraindications, precautions, warnings and guidance on selecting the right drug for a range of conditions.

Drugs usually have three types of names, which are as follows:

• 1.

  Chemical name: It denotes the chemical structure of a drug, e.g. acetylsalicylic acid is the chemical name of aspirin and N-acetyl-p-aminophenol is of paracetamol. It is not suitable for use in a prescription.

• 2.

  Nonproprietary name: It is assigned by a competent scientific body/authority, e.g. the United States Adopted Name (USAN) council. WHO *

  * S Kopp-Kubel. International Nonproprietary Names (INN) for pharmaceutical substances. Bull World Health Organ 1995;73(3):275–279.

  along with its member countries select and recommend the International Nonproprietary Name (INN) for a drug. So, it is uniform throughout the world and denotes the active pharmaceutical ingredient. Few older drugs have more than one nonproprietary name, e.g. the opioid, pethidine and meperidine. The INN is commonly used as generic name. Ideally, generic names should be used in prescriptions because it is economical and generally uniform all over the world than the branded counterparts. Examples are aspirin and paracetamol are generic names.

• 3.

  Proprietary name (brand name): It is given by the drug manufacturers. Brand names are short and easy to recall. Drugs sold under brand name are expensive as compared to their generic version. A drug usually has many brand names – it may have different names within a country and in different countries. Brand names can also be used in prescriptions. Disprin is a brand name of aspirin; Crocin for paracetamol.

  Chemical name	Nonproprietary name	Proprietary name/brand name
  Acetylsalicylic acid	Aspirin	• Disprin • Ecosprin
  N-acetyl-p-aminophenol (Acetaminophen)	Paracetamol	• Crocin • Metacin • Tylenol

They are natural, semisynthetic and synthetic. Natural sources are plants, animals, minerals, microorganisms, etc. Semisynthetic drugs are obtained from natural sources and are later chemically modified. Synthetic drugs are produced artificially.

The different sources of drugs:

• 1.

  Plants:

  • a.

    Alkaloids are nitrogen containing compounds, e.g. morphine, atropine, quinine, reserpine, ephedrine.

  • b.

    Glycosides contain sugar group in combination with nonsugar through ether linkage, e.g. digoxin, digitoxin.

  • c.

    Volatile oils have aroma. They are useful for relieving pain (clove oil), as carminative (eucalyptus oil), flavouring agent (peppermint oil), etc.

  • d.

    Resins are sticky organic compounds obtained from plants as exudate, e.g. tincture benzoin (antiseptic).

• 2.

  Animals: Insulin, heparin, antisera.

• 3.

  Minerals: Ferrous sulphate, magnesium sulphate.

• 4.

  Microorganisms: Penicillin G, streptomycin, griseofulvin (antimicrobial agents), streptokinase (fibrinolytic).

• 5.

  Semisynthetic: Hydromorphone, hydrocodone.

• 6.

  Synthetic: Most of the drugs used today are synthetic, e.g. aspirin, paracetamol.

Drugs are also produced by genetic engineering (DNA recombinant technology), e.g. human insulin, human growth hormone and hepatitis B vaccine.

It is the simplest mode of administration of a drug at the site where the desired action is required. Systemic side effects are minimal.

• 1.

  Topical: Drug is applied to the skin or mucous membrane at various sites for localized action.

  • a.

    Oral cavity: As suspension, e.g. nystatin; as a troche, e.g. clotrimazole (for oral candidiasis); as a cream, e.g. acyclovir (for herpes labialis); as ointment, e.g. 5% lignocaine hydrochloride (for topical anaesthesia); as a spray, e.g. 10% lignocaine hydrochloride (for topical anaesthesia).

  • b.

    GI tract: As tablet which is not absorbed, e.g. neomycin (for sterilization of gut before surgery).

  • c.

    Rectum and anal canal:

    • 1)

      As an enema (administration of drug into the rectum in liquid form):

      • ■

        Evacuant enema (for evacuation of bowel): For example, soap water enema – soap acts as a lubricant and water stimulates rectum.

      • ■

        Retention enema: For example, methylprednisolone in ulcerative colitis.

    • 2)

      As a suppository (administration of the drug in a solid form into the rectum), e.g. bisacodyl suppository for evacuation of bowel.

  • d.

    Eye, ear and nose: As drops, ointment and spray (for infection, allergic conditions, etc.), e.g. gentamicin – eye and ear drops.

  • e.

    Bronchi: As inhalation, e.g. salbutamol, ipratropium bromide, etc. (for bronchial asthma and chronic obstructive pulmonary disease).

  • f.

    Vagina: As tablet, cream, pessary, etc. (for vaginal candidiasis).

  • g.

    Urethra: As jelly, e.g. lignocaine.

  • h.

    Skin: As ointment, cream, lotion, powder, e.g. clotrimazole (antifungal) for cutaneous candidiasis.

• 2.

  Intra-arterial route: This route is rarely employed. It is mainly used during diagnostic studies, such as coronary angiography and for the administration of some anticancer drugs, e.g. for treatment of malignancy involving limbs.

• 3.

  Administration of the drug into deep tissues by injection, e.g. administration of triamcinolone directly into the joint space in rheumatoid arthritis.

Drugs administered by this route enter the blood and produce systemic effects.

Parenteral routes

Routes of administration other than enteral route are called parenteral routes.

Advantages

• ■

  Onset of action of drugs is faster, hence suitable for emergency.

• ■

  Useful in:

  • ■

    unconscious patient

  • ■

    uncooperative and unreliable patient

  • ■

    patients with vomiting and diarrhoea

• ■

  Suitable for:

  • ■

    irritant drugs

  • ■

    drugs with high first-pass metabolism

  • ■

    drugs not absorbed orally

  • ■

    drugs destroyed by digestive juices

Disadvantages

• ■

  Require aseptic conditions.

• ■

  Preparation should be sterile, and is expensive.

• ■

  Require invasive techniques, which are painful.

• ■

  Cannot be usually self-administered.

• ■

  Can cause local tissue injury to nerves, vessels, etc.

Inhalation.

Volatile liquids and gases are given by inhalation for systemic effects, e.g. general anaesthetics.

Advantages

• ■

  Quick onset of action.

• ■

  Dose required is very less, so systemic toxicity is minimized.

• ■

  Amount of drug administered can be regulated.

Disadvantages

• ■

  Local irritation may cause increased respiratory secretion and bronchospasm.

Injections ( fig. 1.1 )

Intradermal route.

The drug is injected into the layers of skin, e.g. BCG vaccination and drug sensitivity tests. It is painful and a small amount of the drug can be administered.

Injectable routes of drug administration.

Subcutaneous (s.c.) route.

The drug is injected into the subcutaneous tissue of the thigh, abdomen, arm, e.g. adrenaline, insulin, etc.

Advantages

• ■

  Self-administration of drug is possible, e.g. insulin.

• ■

  Depot preparations can be inserted into the subcutaneous tissue, e.g. norplant for contraception.

Disadvantages

• ■

  It is suitable only for nonirritant drugs.

• ■

  Drug absorption is slow, hence not suitable for emergency.

Intramuscular (i.m.) route.

Drugs are injected into large muscles, such as deltoid, gluteus maximus and vastus lateralis, e.g. paracetamol, diclofenac, etc. A volume of 5–10 mL can be given at a time.

Advantages

• ■

  Absorption is more rapid as compared to oral route.

• ■

  Mild irritants, depot injections, soluble substances and suspensions can be given by this route.

Disadvantages

• ■

  Aseptic conditions are needed.

• ■

  Intramuscular (i.m.) injections are painful and may cause abscess.

• ■

  Self-administration is not possible.

• ■

  There may be injury to nerves.

Intravenous (i.v.) route.

Drugs are injected directly into the blood stream through a vein. Drugs are administered as

• 1.

  Bolus: Single, relatively large dose of a drug injected rapidly or slowly into a vein, e.g. i.v. ranitidine in bleeding peptic ulcer.

• 2.

  Slow intravenous injection: For example, i.v. morphine in myocardial infarction.

• 3.

  Intravenous infusion: For example, dopamine infusion in cardiogenic shock; mannitol infusion in cerebral oedema; fluids infused intravenously in dehydration.

Advantages

• ■

  Bioavailability is 100%.

• ■

  Quick onset of action, so it is the route of choice in emergency, e.g. intravenous diazepam to control convulsions in status epilepticus.

• ■

  Large volume of fluid can be administered, e.g. intravenous fluids in patients with severe dehydration.

• ■

  Highly irritant drugs, e.g. anticancer drugs can be given because they get diluted in blood.

• ■

  Hypertonic solution can be infused by intravenous route, e.g. 20% mannitol in cerebral oedema.

• ■

  By i.v. infusion, a constant plasma level of the drug can be maintained, e.g. dopamine infusion in cardiogenic shock.

Disadvantages

• ■

  Local irritation may cause phlebitis.

• ■

  Self-administration is usually not possible.

• ■

  Strict aseptic conditions are needed.

• ■

  Extravasation of some drugs (e.g. noradrenaline) can cause injury, necrosis and sloughing of tissues.

• ■

  Depot preparations cannot be given by i.v. route.

Precautions

• ■

  Drug should usually be injected slowly.

• ■

  Before injecting, make sure that the tip of the needle is in the vein.

Intrathecal route.

Drug is injected into the subarachnoid space, e.g. lignocaine (spinal anaesthesia), antibiotics (amphotericin B), etc.

Transdermal route (transdermal therapeutic system).

The drug is administered in the form of a patch or ointment that delivers the drug into the circulation for systemic effect ( Fig. 1.2 ), e.g. scopolamine patch for sialorrhoea and motion sickness, nitroglycerin patch/ointment for prophylaxis of angina, oestrogen patch for hormone replacement therapy (HRT), clonidine patch for hypertension, fentanyl patch for terminal stages of cancer pain and chronic pain, nicotine patch for tobacco deaddiction, etc.

Transdermal drug delivery system.

Advantages

• ■

  Self-administration is possible.

• ■

  Patient compliance is better.

• ■

  Duration of action is prolonged.

• ■

  Systemic side effects are reduced.

• ■

  Provides a constant plasma concentration of the drug.

• ■

  First-pass metabolism is bypassed.

Disadvantages

• ■

  Expensive.

• ■

  Local irritation may cause dermatitis and itching.

• ■

  Patch may fall off unnoticed.

They have been developed to prolong duration of drug action, for targeted delivery of drugs or to improve patient compliance.

• 1.

  Ocusert: It is kept beneath the lower eyelid in glaucoma. It releases the drug slowly for a week following a single application, e.g. pilocarpine ocusert.

• 2.

  Progestasert: It is an intrauterine contraceptive device that releases progesterone slowly for a period of one year.

• 3.

  Liposomes: They are minute vesicles made of phospholipids into which the drug is incorporated. They help in targeted delivery of drugs, e.g. liposomal formulation of amphotericin B for fungal infections.

• 4.

  Monoclonal antibodies: They are immunoglobulins, produced by cell culture, selected to react with a specific antigen. They are useful for targeted delivery of drugs, e.g. delivery of anticancer drugs using monoclonal antibodies.

• 5.

  Drug-eluting stents: e.g. paclitaxel releasing stents used in coronary angioplasty.

• 6.

  Computerized, miniature pumps, e.g. insulin pump for continuous subcutaneous delivery of insulin

Movement of a drug from the site of administration into the blood stream is known as absorption.

It is the fraction of a drug that reaches systemic circulation from a given dose. Intravenous route of drug administration gives 100% bioavailability as it directly enters the circulation. The term bioavailability is used commonly for drugs given by oral route.

If two formulations of the same drug produce equal bioavailability, they are said to be bioequivalent. If formulations differ in their bioavailability, they are said to be bioinequivalent.

Distribution is defined as the reversible transfer of drugs between body-fluid compartments. After absorption, a drug enters the systemic circulation and is distributed in the body fluids. Various body-fluid compartments for a 70-kg person can be depicted as follows:

Many drugs bind to plasma proteins like albumin, α ₁ acid glycoprotein, etc.

Clinical importance of plasma protein binding

• 1.

  

• 2.

  Drugs that are highly bound to plasma proteins have a low volume of distribution .

• 3.

  Plasma protein binding delays the metabolism of drugs.

• 4.

  Bound form is not available for filtration at the glomeruli. Hence, excretion of highly plasma protein bound drugs by filtration is delayed.

• 5.

  Highly protein bound drugs have a longer duration of action, e.g. sulphadiazine is less plasma protein bound and has a duration of action of 6 hours, whereas sulphadoxine is highly plasma protein bound and has a duration of action of 1 week.

• 6.

  In case of poisoning, highly plasma protein bound drugs are difficult to be removed by haemodialysis.

• 7.

  In disease states like anaemia, renal failure, chronic liver diseases, etc. plasma albumin levels are low (hypoalbuminaemia). So, there will be a decrease in bound form and an increase in free form of the drug, which can lead to drug toxicity.

• 8.

  Plasma protein binding can cause displacement interactions. More than one drug can bind to the same site on plasma protein. The drug with higher affinity will displace the one having lower affinity and may result in a sudden increase in the free concentration of the drug with lower affinity.

Chemical alteration of the drug in a living organism is called biotransformation. The metabolism of a drug usually converts lipid-soluble and unionized compounds into water-soluble and ionized compounds, hence not reabsorbed in the renal tubules and are excreted. If the parent drug is highly polar (ionized), then it may not get metabolized and is excreted as such.

Sites: Liver is the main site for drug metabolism; other sites are GI tract, kidney, lungs, blood, skin and placenta.

The end result of drug metabolism is inactivation, but sometimes a compound with pharmacological activity may be formed as shown below:

• 1.

  Active drug to inactive metabolite : This is the most common type of metabolic transformation.

  • Phenobarbitone Hydroxyphenobarbitone

  • Phenytoin p -Hydroxyphenytoin

• 2.

  Active drug to active metabolite

  • Codeine Morphine

  • Diazepam Oxazepam

• 3.

  Inactive drug (prodrug) to active metabolite

  • Levodopa Dopamine

  • Prednisone Prednisolone

Prodrug

It is an inactive form of a drug, which is converted to an active form after metabolism.

Uses of prodrugs (advantages)

• 1.

  To improve bioavailability: Parkinsonism is due to deficiency of dopamine. Dopamine itself cannot be used since it does not cross BBB. So, it is given in the form of a prodrug, levodopa. Levodopa crosses the BBB and is then converted into dopamine.

  

• 2.

  To prolong the duration of action: Phenothiazines have a short duration of action, whereas esters of phenothiazine (fluphenazine) have a longer duration of action.

• 3.

  To improve taste: Clindamycin has a bitter taste, so clindamycin palmitate suspension has been developed for paediatric use to improve the taste.

• 4.

  To provide site-specific drug delivery:

  

Pathways of drug metabolism.

Drug metabolic reactions are grouped into two phases. They are Phase I or nonsynthetic reactions and Phase II or synthetic reactions.

Phase I reactions ( table 1.1 ).

Oxidation: Addition of oxygen or removal of hydrogen is called oxidation. It is the most important and common metabolic reaction.

• ■

  Oxidation reactions are mainly carried out by cytochrome P450, cytochrome P450 reductase, molecular O ₂ and NADPH.

• ■

  There are several cytochrome P450 isoenzymes.

• ■

  They are numbered as 1,2,3,4... (to denote families) and each as A, B, C, D (subfamilies).

• ■

  More than 50% of drugs undergo biotransformation reactions by CYP3A4/5. Other enzymes include CYP2D6, CYP2C9, CYP2E1, CYP2C19, etc.

Table 1.1 ■

Phase I reactions

Oxidation	Addition of oxygen/removal of hydrogen	Phenytoin, phenobarbitone, pentobarbitone, propranolol
Reduction	Removal of oxygen/addition of hydrogen	Chloramphenicol, methadone
Hydrolysis	Break down of compound by addition of water	Esters – procaine, succinylcholine Amides – lignocaine, procainamide
Cyclization	Conversion of straight chain compound into ring structure	Proguanil
Decyclization	Breaking up of the ring structure of the drug	Phenobarbitone, phenytoin

Reduction: Removal of oxygen or addition of hydrogen is known as reduction.

Hydrolysis: Breakdown of the compound by addition of water is called hydrolysis. This is common among esters and amides.

Cyclization: Conversion of a straight chain compound into ring structure.

Decyclization: Breaking up of the ring structure of the drug.

At the end of phase I, the metabolite may be active or inactive.

Phase II reactions ( table 1.2 ).

Phase II consists of conjugation reactions. If the phase I metabolite is polar, it is excreted in urine or bile. However, many metabolites are lipophilic and undergo subsequent conjugation with an endogenous substrate, such as glucuronic acid, sulphuric acid, acetic acid or amino acid. These conjugates are polar, usually water-soluble and inactive.

Table 1.2 ■

Phase II reactions

Conjugation reaction	Enzyme	Examples
Glucuronidation	UDP glucuronosyl transferase	• Aspirin • Morphine
Acetylation	N-acetyltransferase	• Isoniazid • Dapsone
Sulphation	Sulphotransferase	• Paracetamol • Methyldopa
Methylation	Transmethylase	• Adrenaline • Dopamine
Glutathione conjugation	Glutathione transferase	• Paracetamol
Glycine conjugation	Acyl CoA glycine transferase	• Salicylates

Not all drugs undergo phase I and phase II reactions in that order. In case of isoniazid (INH), phase II reaction precedes phase I reaction ( Fig. 1.5 ).

Phases of biotransformation.

Removal of the drug and its metabolite from the body is known as drug excretion. The main channel of excretion of drugs is the kidney; others include lungs, bile, faeces, sweat, saliva, tears, milk, etc.

• 1.

  Kidney: The processes involved in the excretion of drugs via kidney are glomerular filtration, passive tubular reabsorption and active tubular secretion. Glomerular filtration and active tubular secretion facilitate drug excretion, whereas tubular reabsorption decreases drug excretion.

  • Rate of renal excretion = (Rate of filtration + Rate of secretion) – Rate of reabsorption

    • 1)

      Glomerular filtration: Drugs with small molecular size are more readily filtered. The extent of filtration is directly proportional to the glomerular filtration rate (GFR) and to the fraction of the unbound drug in plasma.

    • 2)

      Passive tubular reabsorption: The main factor affecting passive reabsorption is the pH of renal tubular fluid and the degree of ionization. Strongly acidic and strongly basic drugs remain in ionized form at any pH of urine, hence are excreted in urine.

      • a)

        Weakly acidic drugs (e.g. salicylates, barbiturates) in acidic urine remain mainly in ‘unionized’ form, so they are reabsorbed into the circulation. If the pH of urine is made alkaline by sodium bicarbonate, the weakly acidic drugs get ‘ionized’ and are excreted easily.

      • b)

        Similarly, weakly basic drugs (e.g. morphine, amphetamine, etc.) in alkaline urine remain in ‘unionized’ form, hence are reabsorbed. If the pH of urine is made acidic by vitamin C (ascorbic acid), these weakly basic drugs get ‘ionized’ and are excreted easily.

    • 3)

      Active tubular secretion: It is a carrier-mediated active transport which requires energy. Active secretion is unaffected by changes in the pH of urine and protein binding. Most of the acidic drugs (e.g. penicillin, diuretics, probenecid, sulphonamides, etc.) and basic drugs (e.g. quinine, procaine, morphine, etc.) are secreted by the renal tubular cells. The carrier system is relatively nonselective and therefore drugs having similar physicochemical properties compete for the same carrier system, e.g. probenecid competitively inhibits the tubular secretion of penicillins, thereby increasing the duration of action as well as the plasma half-life and effectiveness of penicillins in the treatment of diseases, such as gonococcal infections.

• 2.

  Lungs: Alcohol and volatile general anaesthetics, such as ether, halothane, isoflurane, sevoflurane and ether are excreted via lungs.

• 3.

  Faeces: Drugs like purgatives, e.g. senna, cascara, etc. are excreted in faeces

• 4.

  Bile: Some drugs are secreted in bile. They are reabsorbed in the gut while a small portion is excreted in faeces, e.g. tetracyclines.

• 5.

  Skin: Metals like arsenic and mercury are excreted through skin.

• 6.

  Saliva: Certain drugs like potassium iodide, phenytoin, metronidazole and lithium are excreted in saliva. Salivary estimation of lithium may be used for noninvasive monitoring of lithium therapy.

• 7.

  Milk: Drugs taken by lactating women may appear in milk. They may or may not adversely affect the breast fed infant. Drugs like penicillins, erythromycin, etc. are safe for use but amiodarone is to be avoided in mothers during breast feeding.

The important pharmacokinetic parameters are bioavailability, volume of distribution, plasma half-life (t _1/2 ) and clearance.

Plasma half-life (t _1/2 )

It is the time required for the plasma concentration of a drug to decrease by 50% of its original value ( Fig. 1.6 A). Plasma half-life of lignocaine is 1 hour and for aspirin it is 4 hours.

(A) Plasma half-life of a drug after single intravenous injection. (B) Steady state: achieved after approximately four to five half-lives during repeated administration at a constant rate.

Clinical importance of plasma half-life.

It helps to

• ■

  determine the duration of drug action.

• ■

  determine the frequency of drug administration.

• ■

  estimate the time required to reach the steady state. At steady state, the amount of drug administered is equal to the amount of drug eliminated in the dose interval. It takes approximately four to five half-lives to reach the steady state during repeated administration of the drug. A drug is almost completely eliminated in four to five half-lives after single administration.

• 1.

  Stimulation: Some drugs act by increasing the activity of specific organ/system, e.g. adrenaline stimulates the heart resulting in an increase in heart rate and force of contraction.

• 2.

  Depression: Some drugs act by decreasing the activity of specific organ/system, e.g. alcohol, barbiturates, general anaesthetics, etc. depress the central nervous system.

• 3.

  Irritation: Certain agents on topical application can cause irritation of the skin and adjacent tissues. When an agent on application to the skin relieves deep seated pain, it is known as counterirritant, e.g. eucalyptus oil, methyl salicylate, etc. They are useful in sprain, joint pain and myalgia. They exert their action by

  • ■

    reflexly increasing local circulation in deeper structures.

  • ■

    blocking impulse conduction in the spinal cord.

• 4.

  Cytotoxic: Drugs are selectively toxic for the infecting organism/cancer cells, e.g. antibiotics/anticancer drugs.

• 5.

  Replacement: When there is a deficiency of endogenous substances, they can be replaced by drugs, e.g. insulin in diabetes mellitus, thyroxine in cretinism and myxoedema, etc.

• 1.

  Ligand-gated ion channels (inotropic receptors)

  Table 1.5 ■

  Characteristics of various receptor families

  	Ligand-gated ion channels	G protein-coupled receptors	Enzymatic receptors	Nuclear receptors
  Location	Membrane	Membrane	Membrane	Intracellular
  Effector	Ion channel	Channel or enzyme	Enzyme	Gene transcription
  Examples	Nicotinic, GABA A receptors	Muscarinic, adrenergic receptors	Insulin epidermal growth factor receptors	Steroid, thyroid hormone receptors
  Time required for response	Milliseconds	Seconds	Minutes to hours	Hours

• 2.

  G protein-coupled receptors (GPCRs; metabotropic receptors)

• 3.

  Enzymatic receptors

• 4.

  Receptor-regulating gene expression (transcription factors) or the nuclear receptor

Ligand-gated ion channels (inotropic receptors).

Examples are nicotinic (N _M ) acetylcholine receptors at neuromuscular junction, GABA (gamma amino butyric acid) and glutamate receptors in the CNS.

The onset of action of a drug is fastest through this receptor.

G protein-coupled receptors (GPCRs, metabotropic receptors).

GPCRs are transmembrane receptors which control cell function via adenylyl cyclase, phospholipase C, ion channels, etc. They are coupled to intracellular effectors through G proteins. G proteins are membrane proteins and have three subunits (α, β, γ) with GDP bound to α subunit.

The agonist that binds to the receptor is the first messenger. It results in the formation or recruitment of molecules (second messengers) that initiate the signalling mechanism in a cell. Examples of second messengers are cAMP (generated by adenylyl cyclase), cGMP (generated by guanylyl cyclase), Ca ²⁺ , IP ₃ -DAG (generated by phospholipase C), nitric oxide, etc.

Transmembrane enzyme-linked receptors.

Transmembrane enzyme-linked receptors have enzymatic activity in their intracellular portion. The enzyme is mainly tyrosine kinase, e.g. receptor tyrosine kinases for insulin, epidermal growth factor, etc.).

Transmembrane JAK (Janus kinase)-STAT (signal transducer and activator of transcription) receptors, e.g. receptors for cytokines, growth hormone, etc. These receptors do not have intrinsic enzymatic activity in their intracellular part. On activation, they dimerize followed by their binding to kinases in the cytoplasm, e.g. JAK → phosphorylates tyrosine residues on the receptor → binding of receptor to STAT which gets phosphorylated → dissociation of STAT from receptor → binds to gene to alter transcription.

Nuclear receptors – regulate gene expression.

Examples: receptors for thyroxine, vitamins A and D, sex steroids and glucocorticoids.

Steroids → bind to receptors in cytoplasm → steroid-receptor complex → migrates to nucleus → binds to specific site on the DNA → regulate protein synthesis → response

The pharmacological effect of a drug depends on its concentration at the site of action, which in turn is determined by dose of the drug administered. Such a relationship is called ‘dose–response relationship’.

• 1.

  Graded dose–response: This curve when plotted on a graph takes the form of a rectangular hyperbola, whereas log dose–response curve (DRC) is sigmoid shaped ( Fig. 1.7 A and B).

  

  (A) Dose–response curve. (B) Log dose–response curve. (C) Quantal dose–response curve.

• 2.

  Quantal DRC: Certain pharmacological effects which cannot be quantified but can only be said to be present or absent (all or none) are called as quantal responses, e.g. a drug causing ovulation ( Fig. 1.7 C).

Therapeutic index

Therapeutic index (TI) is an index of drug safety.

$\text{TI =}\frac{{\text{Median lethal dose (LD}}_{\text{50}}\text{) of the drug}}{{\text{Median effective dose (ED}}_{\text{50}}\text{) of the drug}}$

It is the ratio of median lethal dose to the median effective dose ( Fig. 1.8 ).

• 1.

  LD ₅₀ : It is the dose of a drug, which is lethal for 50% of the population.

• 2.

  ED ₅₀ : It is the dose of drug, which produces the desired effect in 50% of the population.

Dose–response curves of therapeutic effect (A) and adverse effect (B).

Higher the value of therapeutic index, safer is the drug, e.g. penicillin G has a high therapeutic index; digitalis, lithium and phenytoin have narrow therapeutic index.

Drug potency

The amount of a drug required to produce a desired response is called potency of the drug. Lower the dose required for a given response, more potent is the drug, e.g. analgesic dose of morphine is 10 mg and that of pethidine is 100 mg. Therefore, morphine is ten times more potent than pethidine as an analgesic. DRC of drug A (morphine) and drug B (pethidine, rightward DRC) as analgesic is compared ( Fig. 1.9 ).

Relative potency of two drugs.

Drug efficacy

It is the maximum effect of a drug, e.g. morphine is more efficacious than aspirin as an analgesic ( Fig. 1.10 ). DRC of drug A (morphine) and drug B (aspirin) as an analgesic is compared.

Relative efficacy of two drugs.

A combination of two or more drugs can result in an increase or a decrease in response.

• 1.

  Route of administration: When a drug is administered by different routes, it commonly exhibits quantitative variations, but sometimes it may also result in qualitative variations in response.

  • a.

    Quantitative variation: Oral dose of drugs are usually larger than intravenous dose (since i.v. route produces 100% bioavailability), e.g. for analgesic effect, intravenous dose of morphine required is 5–10 mg whereas oral dose is 30–60 mg. Onset of drug action following intravenous administration is rapid.

  • b.

    Qualitative variation: The drug may produce an entirely different response when administered by different routes, e.g. magnesium sulphate administered orally produces purgative effect; parenterally, it causes CNS depression and on local application reduces oedema in the inflamed area.

• 2.

  Presence of other drugs: See addition, potentiation, synergism and antagonism.

• 3.

  Cumulation: If the elimination of a drug is slow, then repeated administration of such drug will result in its accumulation in the body causing toxicity, e.g. digoxin, emetine and chloroquine.

• 1.

  Age: In neonates, metabolizing function of liver and excretory function of kidney is not fully developed, e.g. chloramphenicol can cause grey baby syndrome when given to neonates as the metabolizing enzymes are not fully developed. In adults, penicillin G is given 6 hourly, but in infants it is given 12 hourly as the excretory function is not completely developed. In the elderly, renal and hepatic functions progressively decline. The incidence of adverse effect of drugs is also relatively more, and hence drug doses have to be reduced accordingly, e.g. dose of aminoglycosides in elderly is less than normal adult dose.

  • The dose of a drug for a child can be calculated as follows:

    $\text{Young's formula: Child dose =}\frac{\text{Age}}{\text{Age + 12}}\text{× adult dose}$
    $\text{Dilling's formula: Child dose =}\frac{\text{Age}}{\text{20}}\text{× adult dose}$

• 2.

  Body weight and body surface: An average dose of a drug is usually calculated in terms of body weight (mg/kg).

  $\text{Dose =}\frac{\text{Body weight (kg)}}{\text{70}}\text{× Average adult dose}$

  • In obese individuals and in patients with dehydration or oedema, dose calculation on the basis of body weight is not very appropriate. A more accurate method for calculating a dose is on the basis of the body surface area (BSA) of the patient. Nomograms are available to calculate BSA from height and weight of the patient.

  • Since it is inconvenient to calculate BSA, dose is routinely calculated on body weight basis. Dose of anticancer drugs and a few other drugs are calculated on the basis of BSA.

• 3.

  Sex: Drugs like β blockers, diuretics and clonidine can cause decreased libido in males.

• 4.

  Diet and environmental factors: Milk reduces absorption of tetracyclines; fatty meal increases the absorption of griseofulvin (antifungal agent). Cigarette smoke induces hepatic microsomal enzymes and increases metabolism of drugs, such as theophylline. So, the dose of the drug administered may be inadequate in smokers.

• 5.

  Genetic factor: For example, fast and slow acetylators of isoniazid, prolonged succinylcholine apnoea, primaquine induced haemolysis in G6PD deficiency individuals (see p. 17 under metabolism). Other examples are as follows-

  • ■

    Acute porphyria

    • Barbiturates may precipitate attacks of acute intermittent porphyria in susceptible individuals by inducing ALA (aminolevulinic acid) synthase enzyme that catalyses the production of porphyrins.

  • ■

    Malignant hyperthermia

    • In some patients, dangerous rise in body temperature (malignant hyperthermia) may occur especially when halothane–succinylcholine combination is used due to genetic abnormality.

  • ■

    In person with shallow anterior chamber/and or narrow iridocorneal angle, mydriatics may precipitate acute congestive glaucoma.

  • ■

    There is an increased risk of bleeding with coumarin anticoagulants due reduced activity of metabolizing enzyme, CYP2C9.

• 6.

  Psychological factor: Personality of the doctor as well as the patient can affect response to a drug. Some patients respond to inert dosage forms (placebo) in conditions like pain, bronchial asthma, anxiety, etc.

  • Placebo effect: ‘ Placebo ’ is a Latin term that means ‘I will please’. It is a dummy medicine having no pharmacological activity. The effect produced by placebo is called placebo effect. Sugar tablets and distilled water injection are used as placebos.

    • 1)

      Uses

      • a)

        Placebos are used for the relief of subjective symptoms like anxiety, headache, tremors, pain, insomnia, etc.

      • b)

        Placebos are used in clinical trials in order to minimize bias.

    • 2)

      Factors affecting placebo effect are:

      • a)

        Patient factor: Patients with neurotic symptoms often respond to placebos.

      • b)

        Drug factor: The placebo response can be affected by the physical presentation or route of administration of the drug, e.g. colourful tablets, such as red, blue, green and injectable preparations give better placebo effect.

      • c)

        Doctor factor: Personality of the doctor, motivation, way of instruction, doctor–patient relationship, etc. are important factors that also affect response to placebo.

• 7.

  Pathological states:

  • a.

    GI disorders : Achlorhydria reduces the absorption of weakly acidic drugs in stomach by causing their ionization. In malabsorption syndrome, absorption of some drugs is reduced.

  • b.

    Liver disease : In chronic liver diseases, metabolism of drugs is greatly reduced. This will increase bioavailability of drugs having high first-pass metabolism, e.g. propranolol.

  • c.

    Renal failure : Clearance of drugs that are excreted through kidney is impaired, e.g. the incidence of nephrotoxicity and ototoxicity with aminoglycosides is more in the presence of renal failure.

  • d.

    Absorption of iron from the gut is increased in iron deficiency anaemia.

• 8.

  Tolerance: It means ‘need for larger doses of a drug to produce a given response’. Tolerance develops to nasal decongestant effect of ephedrine on repeated use. Patients on organic nitrates for angina develop tolerance on long-term therapy. Tolerance is commonly seen with drugs like morphine, alcohol, amphetamine, etc.

  • a.

    Types of tolerance

    

  • b.

    Mechanism of development of tolerance: It could be pharmacokinetic or pharmacodynamic tolerance.

    • 1)

      Pharmacokinetic tolerance (dispositional tolerance): It is due to reduced concentration of the drug at the site of action – may be as a result of decreased absorption, increased metabolism and excretion. For example, rifampin induces the metabolizing enzyme of oral contraceptives, enhances their metabolism, leading to contraceptive failure.

    • 2)

      Pharmacodynamic tolerance (functional tolerance): The drug effect is reduced, which may be due to downregulation of receptors or decrease in receptor-coupled signal transduction. Repeated use of opioids, barbiturates, etc. results in the development of tolerance due to decrease in the number of receptors (downregulation).

  • c.

    Cross-tolerance: The phenomenon of tolerance exhibited by closely related (structural and mechanistic) drugs is called cross-tolerance, e.g. among nitrates, among opioids, between ether and alcohol.

  • d.

    Tachyphylaxis ( tachy = rapid; phylaxis = protection; acute tolerance ): Repeated use of certain drugs at short intervals may result in rapid decrease in pharmacological response. This is known as tachyphylaxis or acute tolerance, e.g. tyramine, ephedrine and amphetamine. These drugs act by releasing noradrenaline from adrenergic nerve endings. Repeated administration of the drug causes gradual depletion of the neurotransmitter and hence reduction in the response ( Fig. 1.13 ).

    

    Tachyphylaxis. BP, blood pressure.

• 9.

  Drug dependence: See p. 39.

• ■

  Drug not prescribed as per standard treatment guidelines.

• ■

  Unnecessary use of drugs, e.g. antibiotics for viral infections.

• ■

  Underuse of drugs, e.g. not prescribing oral rehydration solution in acute diarrhoea.

• ■

  Incorrect use of a drug, e.g. selection of wrong drug, use of incorrect route and dose of a drug.

• ■

  Use of medicines with doubtful efficacy, e.g. appetite stimulants.

• ■

  Prescribing banned drugs, e.g. cisapride.

• ■

  Use of irrational combinations, e.g. ampicillin and cloxacillin for staphylococcal infections.

• ■

  Prescribing expensive medicines unnecessarily when cheaper, equally effective drugs are available.

• ■

  Polypharmacy.

Adverse effect is defined as any undesirable or unwanted effect of a drug. The WHO-suggested definition of ADR and adverse event (AE) are as follows:

ADR: Any response which is noxious, unintended and which occurs at doses normally used in humans for prophylaxis, diagnosis or therapy of disease, or for modification of physiological function .

AE: Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have causal relationship with the treatment .

• 1.

  H ospitalization.

• 2.

  A irway should be cleared. In comatose patients, there is danger of respiratory obstruction by tongue, secretions and aspiration of vomitus. Hence, patient should be turned to his left lateral side. A cuffed endotracheal tube should be inserted and secretions should be aspirated regularly.

• 3.

  B reathing should be assessed. If there is hypoxaemia, oxygen should be given. Patient may need mechanical ventilation if there is respiratory insufficiency.

• 4.

  C irculation should be assessed (pulse rate and blood pressure) and an i.v. (intravenous) line should be maintained.

• 5.

  To prevent further absorption of poison:

  • a.

    Inhaled poisons (gases): Patient should be moved to fresh air.

  • b.

    Contact poisons: Contaminated clothes should be removed and the body part should be washed with soap and water.

  • c.

    Ingested poisons: G astric lavage can limit the absorption if done within 2–3 hours of poisoning. If patient is unconscious, endotracheal intubation should be done before gastric lavage. Gastric lavage is usually done with normal saline. Other solutions used are lukewarm water, potassium permanganate solution, sodium bicarbonate, etc. Lavage should be repeated till the returning fluid is clear. After the lavage, activated charcoal is administered which adsorbs many drugs and poisons (physical antagonism). Activated charcoal has a large surface area and is highly porous to bind with poisonous material. Gastric lavage should not be carried out in case of poisoning due to corrosives (except carbolic acid), petroleum products (kerosene), convulsants, etc.

    • Mustard, common salt, ipecac syrup, etc. can be used to induce vomiting and prevent further absorption of ingested poisons. However, this method is rarely practiced now.

    • Laxatives like magnesium sulphate or citrate can be used orally to promote elimination of the ingested poison. Oral polyethylene glycol electrolyte solution can be used for whole bowel irrigation of the GI tract in case of poisoning due to iron, lithium, cocaine, heroin, foreign bodies, etc.

• 6.

  To promote elimination of absorbed portion of the drugs:

  • a.

    D iuretics (i.v. mannitol or furosemide) are used to promote the elimination of absorbed portion of the drug. Renal elimination of some of the drugs can be increased by altering the pH of urine, e.g. alkalinization of urine in salicylate poisoning and acidification of urine in amphetamine poisoning.

  • b.

    D ialysis is used in cases of severe poisoning, e.g. lithium, aspirin, methanol, etc.

• 7.

  Symptomatic treatment: Intravenous diazepam 5–10 mg if there are convulsions and external cooling for hyperpyrexia.

• 8.

  Maintenance of f luid and e lectrolyte balance: Hyponatraemia should be treated with i.v. normal saline and hypernatraemia with i.v. furosemide. Hypokalaemia is treated with potassium chloride, oral or slow i.v. infusion. Oral potassium chloride should be diluted in a tumbler of water to prevent intestinal ulceration. Potassium chloride should be given slow intravenously as it has cardiac depressant effect. Rapid injection can cause cardiac arrest and death. Thiazides or furosemide can be used to treat mild hyperkalaemia. Severe hyperkalaemia is treated with 10% calcium gluconate intravenously. Intravenous sodium bicarbonate is used to treat metabolic acidosis.

Note: Mnemonic for general management of poisoning: A to H.

Antidotes for some poisons are listed in Table 1.9 .

Acute toxicity studies

Acute toxicity is carried out in two animal species (one rodent, one nonrodent). Single, graded doses are administered to small groups of animals using two routes – one that is to be used in humans. It is done to determine the general behaviour and median lethal dose (LD ₅₀ ) following exposure to the test drug. LD ₅₀ is the dose required to kill 50% of the animals. It is determined in a 24-hour period after administration of the drug.

Subacute toxicity studies

These are done in two species of animals to determine the maximum tolerated dose, identify target organ of toxicity and nature of toxicities. The test drug is administered daily for a period depending on the duration of treatment in humans. Animals are examined for general effects (food intake, change in the body weight, etc.), biochemical and haematological parameters are monitored; histological examination is done.

Chronic toxicity studies

Drugs are administered in two species (one rodent and one nonrodent) for 6–12 months. Monitoring is done as in subacute toxicity studies.

Special toxicity studies

These include tests for carcinogenicity, mutagenicity and teratogenic effects of the drug. It also includes effects on reproduction.

After completion of preclinical testing of the drug, the company files an investigational new drug (IND) application with the regulatory authority for permission to test the drug in humans. A drug should be scientifically and ethically evaluated by testing in human beings for safety and efficacy prior to its use in man for therapeutic purposes. Such study in humans is referred to as clinical trial. The principles of bioethics should be upheld during clinical trials. They include autonomy, beneficence, nonmaleficence and justice. Clinical trials are conducted in four phases, I–IV. Usually, the information obtained from one phase is analysed before proceeding to the next phase.

International Council for Harmonization – Good Clinical Practice (ICH–GCP) guidelines is an international ethical and scientific standard for designing, conducting, monitoring, terminating, auditing, reporting and recording trials. It ensures that the data generated from the trials is credible, accurate and the rights, integrity and confidentiality of the participants are protected.

Prior to enrolling the patient in the trial, the investigator should obtain informed consent from the subject. It is a process by which a subject voluntarily confirms his/her willingness to participate in a trial after having been informed of all aspects of the trial relevant to the subject’s decision to participate in the trial. The consent should be obtained by the investigator in the subject’s language without exerting undue influence. The informed consent is documented by means of a written, signed and dated (by both investigator and subject) informed consent form. If a subject is illiterate, his legally accepted representative or an impartial witness should be present during informed consent process. The thumb impression of the subject is taken and his legally accepted representative should sign and date the informed consent form. In case of young children and mentally ill patients, consent is obtained from their guardian or legal representative.

It is a committee or board designated by the institution to review research proposals and conduct periodic review of research involving humans so as to ensure the protection of the rights and welfare of human subjects. The number of persons in an ethics committee is about 7–15. A minimum of five persons are required to form the quorum.

Composition

• 1.

  Chairperson (from outside the institution to maintain independence of the committee)

• 2.

  Basic medical scientists (preferably one pharmacologist)

• 3.

  Clinicians

• 4.

  Legal expert or retired judge

• 5.

  Social scientist/philosopher/ethicist/theologist

• 6.

  Lay person from the community

• 7.

  Member secretary

It is a process where the subjects are randomly assigned to treatment groups in a clinical trial using a chance mechanism. This is usually done by a computer. The investigator has no role in deciding the allocation of a particular treatment to a particular patient in the trial. Randomization is done to avoid bias in the constitution of trial group.

The purpose of blinding in a trial is to eliminate bias. It is done to conceal the identity of the drug from the investigator and the subject. It could be single blind or double blind.

In a double blind trial, both the investigator and the subject do not know the identity of the drug administered to the subject. In a single blind trial, the subject is unaware of the identity of the drug administered to him. A randomized double blind trial is a standard design for most of the clinical trials.